This is a biology book written by a physicist who performs research in cellular biology. I picked it up and started reading it, but I got stuck somewhere in the chapter on thermodynamics. So I contacted Mike Elzinga, a frequent commenter on PT, and asked him to explain something. In the process, I somehow conned him into writing a review of the book for PT. I will add only that the figures in the book are less than desirable on a Kindle (and some are fairly crude hand sketches), and I indeed intend to read Chapter 7 again when I get a chance.

Here, with appreciation, the book review.

by Mike Elzinga

This book, by Peter M. Hoffmann of Wayne State University, explains “How molecular machines extract order from chaos,” in the words of its subtitle.

That chaos of which Hoffmann speaks is the thermal motion of molecules that we call heat. Yet our historical understanding of the randomness of thermal motions suggests that it is counterintuitive to expect order to emerge out of such chaos, let alone any regularity that has the characteristics of life.

There is also a persistent meme in our popular culture that propagates the misconception that the second law of thermodynamics says everything tends toward disorder and disintegration. Life is perceived to be the “opposite” of disorder; therefore, living organisms rely on some external agency that bucks the trend toward chaos. Not only is that meme completely wrong; evolution found a way to harness the chaos. Hoffmann, while describing the use of tools like atomic force microscopy, shows us how molecules in the cells of living organisms do it.

The question “What is life?” has been around since at least the time of the early Greeks. The formulations of the answer to this question have ranged from animism, in which the entire universe is imbued with a “life force” that causes everything to move and change, to “vitalism,” which adds something extra to living organisms that animates and distinguishes them from non-living objects, to “atomism” which attributes the actions of life to the ceaseless motions of unseen particles that are the ultimate building blocks of everything.

Chapter 1. Hoffmann’s book is divided into nine chapters plus an introduction and an epilogue. He begins Chapter 1, “The Life Force,” with a compressed historical overview of vitalism and atomism, beginning with Aristotle, Democritus, and other early Greeks, focusing primarily on atomism and vitalism.

He traces atomism and vitalism through early medicine and magic, until they collided with mechanical philosophy beginning around the 1600’s. At this point, the issue of what animates life was brought into much sharper focus. Throughout the seventeenth, eighteenth, and nineteenth centuries, the questions about the role of the blood, air, and food in the animation of living organisms began to change the way research is done. The discoveries of oxygen, carbon dioxide, the nature of combustion, animal heat, electricity, physics, and chemistry all entered the picture, as did “irritability” and Mary Shelley’s Frankenstein.

Irritability was one of five “vital forces” that German biologist Carl Friedrich Kielmeyer thought was acting on living beings. He called these vital forces “the physics of the animal realm” Irritability was the ability of muscles to move on their own when disconnected from their animal hosts. This phenomenon attracted considerable ghoulish attention from scientists who engaged in increasingly gruesome experiments using high voltage electricity applied to dead animals and humans. These activities prompted Shelley’s horror story of a scientist creating life from dead flesh.

The experiments demonstrating conservation of energy by Herman von Helmholtz vanquished the vital force and put biology back on the track of mechanism by the end of the nineteenth century, at least temporarily.

But now the problem of complexity and order from chaos is brought back into focus. Darwin’s theory of evolution had, at that time, no mechanism to produce variation and novelty. Mendel’s work was discovered only later. Blending of traits didn’t work. Did evolution need an injection of a life force after all?

Chapter 1 is a whirlwind sketch of a much larger history of “the life force,” and it is by no means complete. However, for those who may not have read much of the history of science, Chapter 1 sets the stage for the questions that Hoffmann addresses later in his book. What is a life force? How is it attached to the body? Where is it attached? How does it animate the body? How can atomism work in the face of thermal chaos?

Chapter 2, “Chance and Necessity,” discusses the concepts of probability, statistics, and randomness. Hoffmann again delves into some history here. The central question of chance versus necessity is highlighted, specifically, how can regularity and law emerge out of chaos? We see again the case being made - for example, by Teilhard de Chardin - for some external guiding force that nudges the underlying chaos toward some purposeful goal.

Erwin Schrödinger, one of the discoverers of quantum mechanics, puzzled over how molecules can withstand thermal motions, and he came to essentially the wrong conclusion that cells were made stable by strong chemical bonds.

This conclusion presented a conundrum: the bonds would have to be so strong that the cell would essentially be a solid. There are, however, no solids in the cell. This conundrum is taken up later in the book. If cells are soft and squishy, why are they not torn apart by thermal motion? This important question leads to how processes within the cell actually work.

Chapter 3, “The Entropy of a Late-Night Robber,” is a short chapter on energy, entropy, and the laws of thermodynamics, particularly the second law.

Hoffmann relates a personal incident, in which he was robbed of ten dollars at gunpoint, and uses it to illustrate the spreading around of money as an analogy for the spreading around of energy. He also uses that old analogy of a messy room, in which clothing and other items in various locations represent energy microstates.

The messy room analogy has been partly responsible for the frequent misconception that entropy means “disorder.” Hoffmann repeatedly makes it very clear that entropy is not disorder, a point that should be noted carefully. He also makes the physicist’s proper connection of entropy with “information.”

Hoffmann introduces one of the “free energies” of thermodynamics, specifically the Helmholtz free energy, F = E - TS. In this equation, E is the internal energy of the thermodynamic system, T is its temperature, and S is its entropy. The Helmholtz free energy is chosen because it applies to thermodynamic processes taking place at constant temperature and volume, and all the processes going on in cells take place at constant temperature.

Hoffmann shows a simplified free energy vs. temperature graph for water transitioning through its freezing point, and he explains that the free energy is minimized during this transition. The basic idea is that a competition between the export of entropy and the lowering of internal energy results in making this free energy a minimum.

I found Hoffmann’s explanation a little unclear, and I did a double-take after reading the caption under that graph. There is nothing in the graph that shows the free energy going through a minimum, and I suspect this may cause some confusion for the reader.

The Helmholtz free energy remains constant for thermodynamic transitions taking place at fixed temperature and volume, in this example, right at the freezing point. So when a system is at its freezing point, the Helmholtz free energy remains constant while the material freezes, and there is no discontinuity in the graph, merely a change in slope coming out of the freezing point. The entropy is the negative of the slope of a Helmholtz free energy vs. temperature curve, the smaller slope being on the solid side, the bigger slope on the liquid side.

My own personal preference in describing thermodynamic processes to general audiences is to avoid the various thermodynamic potentials and go directly to basic mechanisms that a high school student would be familiar with.

For example, in the case of a freezing system such as this, molecules are falling deeper into mutual potential energy wells and staying there. To stay there requires that energy be shed from the molecules, and that energy leaves the system in the form of radiation or by way of momentum transfers to molecules that make up a containing vessel.

That departing energy spreads out among many more energy microstates in the surrounding environment; the entropy of the environment increases. Meanwhile, the molecules that are now bound together have not only less energy, they have access to fewer energy microstates because they can only vibrate in position; their entropy has therefore decreased. The combined entropy changes end up as a net overall increase in the entropy of the universe.

It is a general property of matter in the universe that it clumps, and clumping requires the shedding of energy. This is the second law of thermodynamics at work.

I don’t think Hoffmann’s explanations in this chapter will detract from later parts of the book, especially when he discusses enzymes or other catalysts mechanically distorting molecules, thereby pulling down potential energy barriers to molecular binding, or ATP energy dumps that are used to separate bound molecules.

The rest of Chapter 3 introduces Hoffmann’s use of the expression “molecular storm,” which he uses in later chapters. It is an apt description, and he finishes off the chapter emphasizing that “life is a near-equilibrium, tightly controlled, open, dissipative, complex system.” “Near-equilibrium” is an important modifier here. Systems far from equilibrium tear things apart; the processes in cells are highly efficient compared to man-made engines and nature’s tornadoes.

Chapter 4, “On a Very Small Scale,” describes the realm in which the cell processes take place. This is the nanometer scale, in which electrical, mechanical, and chemical energies compete with the kinetic energies of thermal noise. But it is in this realm, as Hoffmann points out, that there is any hope of solving the question about what life is.

There is a good discussion here about time and energy scales, energy landscapes, collective behavior, entropic forces, bonding, exclusion zones, and a number of other important phenomena that contribute to the behaviors of molecules at this scale. These turn out to be important in solving the riddle of life. The solution to Schrödinger’s riddle is also addressed.

To emphasize more graphically the points Hoffmann is making about this nanoworld, I would recommend a little high school level physics/chemistry exercise that scales up the charge-to-mass ratios of protons and electrons to kilogram-sized masses separated by distances on the order of 1 meter. When one calculates the energies of interaction of such masses, one comes up with energies on the order of 1026 joules, or 1010 megatons of TNT.

Imagining oneself sitting among such scaled-up charges and masses gives some perspective on the energy-to-mass ratios at the molecular level, and what it would be like to be the size of a molecule sitting among atoms and molecules. This perspective shows the silliness of the creationist’s tornado-in-a-junkyard argument against molecular evolution. Junkyard tornadoes are puny compared to the interaction energies of masses with the scaled up charge-to-mass ratios of protons and electrons; the kinetic energy of a kilogram mass moving at the maximum wind speed of an EF5 tornado is about 104 joules.

If we scale ourselves down to the size of a molecule inside the cell, we are dealing with energies on the order of a few hundredths to a few tenths of an electronvolt, very large energies compared to that of our now tiny selves. Atomic force microscopy can measure the force with which a “walking” molecule can pull. These forces are on the order of piconewtons (10-12 newton). A potential energy gradient of about 0.01 electronvolt over a distance of 1 nanometer is a force on the order of 1 piconewton. Advocates of “vital forces” and “intelligent intervention” will have to explain how these non-physical “forces” escape detection even though they can still push atoms and molecules around.

One of the important points that Hoffmann makes in this chapter is the relationship between quantum mechanical effects and thermal noise. In the realm and temperature of the cell, quantum mechanical effects are completely swamped by thermal noise. Much of the research on quantum computing has to take place at very low temperatures, far too low for any living system. As Hoffmann makes clear at this point, essentially all of molecular biology can be explained using classical physics.

Chapter 5, “Maxwell’s Demon and Feynman’s Ratchet,” deals precisely with these topics. The question, of course, is whether or not it is possible to violate the second law of thermodynamics. Does a vital force have to be introduced? What does it take to make a ratchet, bombarded by the impacts of photons and particles, turn in only one direction?

A clear understanding of the demon and the ratchet is the key to understanding the mechanism behind the directionality of processes taking place within the cell. What is that mechanism that extracts order out of chaos?

Hoffmann tantalizingly leaves the question open in preparation for the next chapter.

Chapter 6, “The Mystery of Life,” starts out with the declaration, “Thou shalt not violate the second law.” Here Hoffmann lays out some of the details of what has to be done, and how it is done by enzymes, allostery, and the release of energy into a ratchet at just the proper time. As you would expect, it takes energy input to make a ratchet being bombarded by a molecular storm turn in one direction; there is no violation of the second law. The molecular storm does most of the work, and a small input of energy from a molecule like ATP keeps the ratchet from “slipping backward” in what Hoffmann refers to as a “reset step.”

This chapter describes in considerable detail just how molecules like kinesin can walk along a nanotube rail; this is where we actually see the physics of how these molecules extract order out of chaos.

Hoffmann contrasts here the difference between a robust “molecular Hummer” plowing through a molecular storm, and a floppy molecular system that harnesses the energy of the storm. He shows how Nature favors the latter.

Near the end of the chapter, Hoffmann shows a very interesting graph of the speed of a molecular motor as a function of temperature . He explains the importance of thermal motion in making it work. As someone who has worked in the field of condensed matter physics, I could certainly appreciate this explicit example of the very sensitive dependence of life on temperature. The phenomena of hypothermia, hyperthermia, and the chirp rates of crickets and cicada have been known for at least a century. To a physicist or a chemist, temperature dependent phenomena such as these are very strong clues about the mechanisms of life.

Chapter 7, “Twist and Route,” is the longest chapter in the book; it is packed full of details about a number of other molecular systems that waddle, walk, stride, rotate, pump, and replenish ATP. The reader may want to reread this chapter a number of times to get the details.

Some of the experimental techniques are described in this chapter. One of the stories that particularly caught my attention was the section entitled “ATP Synthase and the Amazing Spinning Baton.” In order to prove that the ATP synthase is a rotary machine, biochemist Hiroyuki Noji and coworkers at the Tokyo Institute of Technology actually attached a magnetic bead to one of the units of the synthase and used a rotating magnetic field to turn the “handle.” When rotated clockwise, the synthase produced ADP; when rotated counterclockwise, it produced ATP!

Chapter 8, “The Watch and the Ribosome,” gets into the question of how such molecules came to be. The watch reference is, of course, to William Paley.

Hoffmann recounts Paley’s musings on what would be the nature of watches that could reproduce; he follows these musings to point out that Paley was misguided on the topic of reproduction. Would reproducing watches evolve? If they did, what does that say about the similarities among watches and their ability to “improve”? Evolution introduces chance. What if watches evolved an internal “purpose” of efficient reproduction? You would still need an external agent to select the best watches from among all the offspring of those that reproduced. Without an external agent, a watch would eventually stop being a watch. What does this then say about the artificer that designed the first watch or watches? Pursuing this line of thinking illuminates some of the major problems with locating the original intent of a designer that is now lost in the mists of the evolutionary history of watches.

The basic question is, “How do molecules evolve?” Is there a form of natural selection that applies to molecules in the way that natural selection applies to populations of living organisms? Hoffmann makes a good case for molecules evolving; in fact, given their environment, there is no other way.

Chapter 9, “Making a Living,” takes us into some broader issues having to do with regulation, systems biology and regulatory networks, emergence, reductionism, and the relationships between biologists and physicists.

Basically the issue about cells is that no cell is an island; they work in conjunction with other cells, within large systems of cells, and within a larger environment.

On the issue of holism versus reductionism, Hoffmann sees this philosophical debate as a nonissue for most scientists. I agree. As Hoffmann also observes, holism and reductionism are two sides of the same coin; we take things apart to find out how they work, but we have to put them back together again in order for them to have the properties by which we identify and describe them. A cow may be ultimately reducible to quarks, but quarks are not a cow, and you cannot predict a cow from knowing the properties of quarks. You can’t even predict a house from the properties of bricks or stones. There are no formulas for cows based on particle physics just as there are no formulas for a house based on the properties of bricks or stones.

Most complex systems, such as those we find in biology, are momentarily frozen accidents resulting from a vast sequence of contingencies. Another way to state this is that the unique properties of complex things emerge from their contingent development, the contingent relationships within themselves, and their relationships with their environment and with the other contingent things that see them and describe them.

Epilogue. Readers of Douglas Adams’s Hitchhiker’s Guide to the Galaxy will recognize the title of the Epilogue, “Life, the universe, and everything.”

Hoffmann notes that we are changing our entire perspective on the structure of the universe as a result of what we are learning about the processes in the cell. He notes also that “the universe is not a victim of the second law of thermodynamics. If this were so, the universe would just contain diffuse nebulae of hydrogen and helium.” In other words, if matter did not continue to condense, the universe would contain no stars, no planets, and no life.

Summary. Other features of the book include a good index, a useful glossary, a nice list of additional sources, and a suggested reading list. The sources are listed as they come up chapter-by-chapter, and the reading list is organized by topic. These provide additional resources for anyone who wants to dig deeper into this subject.

All in all, I found the book an enjoyable read. Despite my physicist quibbles about the description of the Helmholtz free energy in Chapter 3, I highly recommend the book as a good overview of the history, the physics, and some of the philosophical issues surrounding the question, “What is life?” I am a layman in the biology, but I found Hoffmann’s physical descriptions and the physical mechanics of these “ratchets” easy to grasp.

P.S. In addition to his book, you may find an online video of Hoffmann giving a talk covering some of the topics of his book.

Mike Elzinga is a retired physicist whose career was in pure and applied research. He worked in low temperature physics and superconductivity, optics and holography, ultrasonic imaging, solid state devices in extreme radiation environments, and the development of infrared detecting CCD imagers.